SAMe is an important naturally-occurring substance in mammals. It plays an essential role in regulating the cell and the various biochemical processes that occur within it, from the expression of genes to the action of hormones and neurotransmitters.
SAMe is the principal methyl donor in mammals. The process of methylation is essential to building molecules and controlling the reactions between them. Most organic molecules are built along a carbon skeleton comprised of chains, rings, or other conformations of carbon atoms. The “vertebra” of this skeleton is an atom of carbon attached to three hydrogen atoms, forming a methyl group (CH3). When organic molecules are assembled, it takes a certain amount of energy to attach a methyl group to a growing carbon chain. SAMe provides this energy. It contains within its structure the capacity to catalyze the transfer of single carbon or methyl groups in the most energy efficient manner. This capacity conferred survivability to the earliest self-organizing life forms and has made SAMe an important methyl donor in virtually every living organism on Earth, from single-cell prokaryotes to higher primates and human beings.
SAMe is the sulfonium form of the condensation of the high-energy compound ATP (adenosine triphosphate) and the essential amino acid methionine. Its structure is set forth below in Formula I:

SAMe is formed within the body from methionine and ATP in a reaction catalyzed by methionine adenosyl transferase. The presence of the sulfonium ion activates the methyl group adjacent to it. This methyl group may be transferred to the amino and hydroxy acceptors of a variety of molecules, such as guanidoacetate to yield creatine, ribosomal and transfer RNA to yield methylated RNA, and norepinephrine to yield epinephrine. In addition to such transmethylation reactions, SAMe plays an important role in transsulphuration and transaminopropylation reactions, as well. For example, SAMe is a substrate of a specific lyase that converts the lyase to methylthioadenosine (MTA) and homoserine; it can be an aminoacidic chain donor in the biosynthesis of biotin; it can be a donor of the adenosyl moiety; it can be a promoter of lysin-1, 3-amino mutase, threonine synthetase, pyruvate formate lyase, and N5-methyltetrahydrofolate-homocysteine methyltransferase; it can be an inhibitor of H ribonuclease, methylene tetrahydrofolic reductase, and ethanolaminephosphate cytidyltransferase; it is important for bacterial and leukocyte chemotaxis; and it is required in the prokaryote and eukaryote restriction and modification system of DNA. U.S. Pat. No. 6,020,139 (“the '139 patent”), the disclosure of which is incorporated herein by reference, describes additional biochemical pathways by which SAMe is metabolized in the body.
On a broader level, SAMe regulates gene expression and helps prevent genetic mutations; it maintains mitochondrial function; it participates in phospholipid synthesis and maintains the integrity of cell membranes; and it regulates neurotransmitters such as serotonin, dopamine and epinephrine (Adrenaline), and hormones such as estrogen and melatonin.
Administering SAMe to subjects has been found to have a variety of salutary effects. U.S. Pat. No. 5,166,328 and U.S. Application No. 2002/0025926, the disclosures of which is incorporated by reference, describe some of these effects in the brain: it inhibits neuron death following ischemia; it improves the utilization of glucose in the brain; it inhibits brain edema; it improves EEG and evoked potential findings by normalizing them; and it improves motor function, such as that impaired by stroke. SAMe has been found, for example in meta-analyses of multiple drug studies, to enhance emotional well-being and is as effective as many common prescription drugs—tricyclics such as Elavil® (amitriptyline HCl) and Norpramin® (desipramine hydrochloride), and Selective Serotonin Reuptake Inhibitors (SSRIs) such as Prozac® (fluoxetine hydrochloride), Zoloft® (sertraline hydrochloride), and Paxil® (paroxetine hydrochloride)—in treating depression, but with significantly fewer side effects than any of these drugs. SAMe has also been used to treat anxiety, chronic pain, arthritis, rheumatoid fibromyalgia, Chronic Fatigue Syndrome, cognitive difficulties associated with Alzheimer's Disease, neurovascular disease and neurological conditions associated with AIDS. In addition to diseases of the central and peripheral nervous system, SAMe has been found to improve diseases of the joints, cardiovascular system, and liver.
Current SAMe therapy has serious shortcomings. SAMe is expensive. Preparations of SAMe cost (as of early 2001) anywhere from $1.00 to $2.50 for a single 200 mg dose. Such a dose, moreover, can benefit most subjects only mildly; treating depression, neurodegenerative disorders, and other serious conditions can require a dose of 1,600 mg or more, one to three times a day, making long-term treatment too expensive for most consumers.
SAMe is difficult to store. It is highly reactive and very hygroscopic; moisture or heat quickly degrade it. At 35° C. (95° F.), for example, SAMe will remain stable for only 8-10 hours. Making a stable SAMe salt, with tosylate, disulfate tosylate, or 1,4-butanedisulfonate, for example, increases manufacturing cost and partially accounts for the high cost of SAMe.
SAMe is difficult to administer. In most cases, SAMe is administered orally. It is sold as an over-the-counter preparation, making administration via other routes, such as by injection, suppository, or other parenteral routes, impractical or undesirable. When administered orally, some of the SAMe is consumed by intestinal flora, some of which may be pathogenic bacteria. Poor absorption of SAMe in the stomach and in the body requires the administration of large doses of SAMe to achieve the intended effect. Because SAMe is expensive, this is a serious shortcoming. As a result, much of the SAMe administered orally does not enter the bloodstream, and pharmacokinetic studies have failed to show that exogenous SAMe enters the intracellular compartment intact. SAMe contains several water-soluble groups, such as hydroxyl groups, amino groups, a sulfonium group, and a carboxyl group, and as a result has only a weak tendency to cross the lipid-rich membrane of the cell.
Administering SAMe orally can lead to serious side effects in certain individuals. SAMe can create or exacerbate an over-methylated state, leading to a manic state in individuals suffering from bipolar disorder, for example. SAMe donates a methyl group to become S-adenosyl-L-homocysteine; a hydrolase then cleaves this molecule, yielding adenosine and L-homocysteine. High levels of homocysteine have been linked to cardiovascular and neurovascular disease, and can be dangerous for individuals with high blood pressure and angina. In many susceptible individuals, administering SAMe orally may disturb the body's natural regulation of these reactions, resulting in elevated levels of homocysteine.